The goal of this research program is to develop and apply state-of-the-art computation methods to understand stereoselectivity and to design new stereoselective reagents and catalysts. The control of stereoselectivity is an essential feature of efficient synthesis, and this program provides explanations of the origins of these selectivities and builds on these to predict new reagents and catalysts for regioselective and stereoselective reactions. These are critical elements in the synthesis of effective pharmaceutical agents. This renewal of GM36700 is built on the achievements of the last grant period. Collaborations with many synthetic laboratories around the world have kept our attention focused on problems that are central to progress in organic synthesis. The grant has been a training vehicle for a large number of graduate students, postdocs, and visitors to our laboratories from synthetic groups, and these people have become leaders in computational understanding of organic and pharmaceutical chemistry. The specific aims for the new grant period are: Aim 1: Development of computer program and resources to provide accurate predictions of stereoselectivity for large and flexible molecules. To combine the quantum mechanics at various levels, conformational searching with force fields, and analysis tools for the understanding of stereoselectivity and design of new catalysts and ligands, as well as to access the many computers and clusters available to our group, a computer program/interface called DESIGNMAKER will be created. Aim 2: Explorations of asymmetric organocatalysis and design of new catalysts. Nucleophilic, hydrogen-bonding, and bifunctional catalysts as well as cascade reactions involving organocatalysts will be studied, and new versions will be designed. Aim 3: Exploration of transition metal catalyzed asymmetric reactions. Rh, Mo, Ru, Pd, and Ni-catalyzed hydrogenations, allylic substitutions, and asymmetric coupling reactions will be explored in order to establish the origins of transition metal catalysis of regioselective and stereoselective reactions. Aim 4: Collaborative design and testing of new reagents and catalysts for stereoselective reactions. Ongoing collaborations with Carlos Barbas (Scripps), Paul Wender (Stanford), Yonqui Sun, Ian Davies, Thorsten Rosner, Shane Krska (Merck), Samuel Danishefsky (Columbia-SKMI), Timothy Jamison and Stephen Buchwald (MIT), and others will drive the development of new technology and increase our understanding of stereoselectivity of many different types of reactions. PUBLIC HEALTH RELEVANCE: The goal of this research program is to develop and apply state-of-the-art computation methods to understand stereoselectivity and to design new stereoselective reagents and catalysts. The control of stereoselectivity is an essential feature of efficient synthesis, and this program provides explanations of the origins of these selectivities and builds on these to predict new reagents and catalysts for regioselective and stereoselective reactions. These are critical elements in the synthesis of effective pharmaceutical agents.